Oils have many advantageous properties. Many cosmetic compositions contain fats and oils or materials derived from such fats and oils that serve as emollients and/or lubricants therein. Exemplary of such materials are triglyceride esters, fatty acids, fatty alcohols, soaps, detergents, cationic antiseptic and softener rinses, alkyl fatty acid esters, polyhydric alcohol esters, ethoxylated fatty alcohols, ethoxylated fatty ethers, ethoxylated sorbitan esters, branched-chain high-molecular weight alkyl esters, lanolin-derived fatty acids and fatty alcohols, other lanolin derivatives, and the like. In the pharmaceutical field, oils and fats are also used as emollients and/or lubricants in topical compositions, castor oil is useful as a cathartic, while chaulmoogra oil is used to treat Hansen's disease. Also, corn, sesame and cottonseed oils, for example, are employed as carriers for fat-soluble substances.
Marine animal oil compositions, in particular, have been suggested for a variety of uses as dietary supplements. For example, marine oil compositions are alleged to decrease cholesterol and triglycerides levels in humans, decrease prostaglandin synthesis, inhibit platelet aggregation and the like. Moreover, food processing concepts are being investigated to increase dietary intake of marine oils. Some proposals include incorporating fish oils into a wide variety of products, such as pastes and spreads, butter analogs and margarines, salad dressings, dairy foods, oils and oil blends, sausage, and smoked and spiced foods. Marine oil compositions or derivatives there of have also been used in both cosmetic and therapeutic topical formulations. For example, shark liver oil has been determined to be useful for the temporary protection of minor cuts, scrapes, burns and sunburn, and for the prevention and temporary protection of chafed, chapped or windburned skin and lips.
A non-fatty acid/ester component of marine oil compositions, often isolated, hydrogenated and included in topical compositions, is squalene, an unsaturated hydrocarbon C.sub.30 H.sub.50. Squalene is also a component of adult human skin surface lipids. Squalene, itself, is not typically used in topical compositions due to its susceptibility to oxidation, resulting in formation of undesirable oxidation products. Primarily for this reason, squalene (hydrogenated squalene, also found in high concentrations in human skin surface lipids and obtained through chemical processing of squalene) is the hydrocarbon most often included in topical compositions.
While oral dosage forms containing oils, such as fish oils, have been developed and marketed as dietary supplements, the usefulness of topical preparations containing these oils has been limited by the unpleasant odor associated with such oils. When a composition is applied topically, any odor associated therewith becomes associated with the skin to which it is applied. As a result, consumer acceptability of topical compositions is highly influenced by the aroma thereof. Consequently, topical compositions having a malodorous oil component would not enjoy success in the marketplace.
The "off" or "rancid" odor associated with oils is produced, in part, by oxidation of polyunsaturated fatty acids contained therein. Since highly unsaturated fatty acids occur in greater proportion in marine animal oils than in common land animal and vegetable fats and oils, rancidity is a greater problem when using marine animal oils. Oxidation of polyunsaturated fatty acids leads to the formation of hydroperoxides. The decomposition products of these hydroperoxides, such as aldehydes resulting from oxidation of marine animal oils, exhibit the unpleasant odors characteristic of rancid oils. Certain decomposition intermediates have also been suggested to contribute to the unpleasant odor of some oxidized oils.
The "inherent" or "bland" odor of oils does not appear to arise from volatile components of oil compositions, which could be easily removed therefrom. Instead, these odors appear to be characteristic of the fatty acids or long-chain hydrocarbons associated therewith in natural oil compositions. In fish oils, for example, the "fishy" odor is postulated to be the result of interaction during oxidation between nitrogenous moieties and unsaturated glycerides present in the oil composition. Another theory regarding the source of the odor is that the unsaponifiable fraction (i.e., 5 hydrocarbon, sterol, methyl sterol, long-chain alcohol, triterpene alcohol, pigment, trace materials and the like) of the oil composition is the component with which the "fishy" odor is associated. In any event, this odor is not permanently removable even by drastic steam deodorization procedures (i.e., prolonged vacuum treatment at elevated temperatures, such as from about 230.degree. to 260.degree. C.). The odor returns upon exposure of the "deodorized" oil to oxygen.
Since marine oils are capable of imparting advantageous properties to topical compositions, efforts have been made to overcome the aroma problem. These efforts were complicated by the fact that many processes alter the composition of fats and fatty acids. Exemplary processing techniques are refining, high temperature clay bleaching, high temperature-high pressure fat splitting, distillation of fatty acids, molecular distillation of monoglycerides, transesterification reactions and partial hydrogenation. Alterations arising from processing include cis-trans isomerization, conjugation of polyunsaturates, polymerization, dehydration and the like.
Two strategies have emerged for using malodorous oils in topical compositions. In the first, only amounts of oil small enough not to adversely impact the odor of the complete topical composition were used. This strategy is not effective when higher concentrations of oil are required or desireable to impart advantageous properties to topical compositions.
Alternatively, to increase the percentage of oil which may be used within commercially acceptable topical compositions, chemical deodorization was explored. Barlow S. M. and Stansby M. E., eds., "Nutritional Evaluation of Long-Chain Fatty Acids in Fish Oil", page 20 Academic Press, London, 1982 describe a deodorization process featuring steam distillation conducted under a vacuum. The primary operating unit is a steel shell having trays disposed therein, maintained at from 2 to 5 mm Hg absolute pressure. The oil composition is heated to a process temperature of about 220.degree. to 250.degree. C. by steam, and volatiles, which adversely impact oxidative stability, are removed from the unit. Typical refining processes are also discussed in "Nutritional Evaluation of Long-Chain Fatty Acids in Fish Oil" at pages 13-20. Such refining processes include crude oil storage (to remove oil insolubles), degumming, neutralization, water washing, drying, bleaching, filtration, deodorization, polishing and the like.
Problems arose during the deodorization and refining processes, however, in that the processing steps changed the chemical composition of the oil itself (i.e., the composition being deodorized that resulted from minimal refining of the oil). For example, natural antioxidants, such as the various tocopherols which constitute vitamin E, were often either removed from the oil composition, broken down or chemically altered to such an extent that those antioxidants were functionally destroyed or impaired during deodorization or other oil processing. See, for example, Bailey's Industrial Oil and Fat Products, Volume 1, Fourth Ed., page 75, Daniel Swern, ed., John Wiley & Sons, New York, 1979. Caustic and steam oil refining processes remove at least a portion of tocopherol compounds from oil compositions. Carbon treatment of oil compositions also results in antioxidant removal. It has been determined that even small amounts of antioxidant may be sufficient to cause an increase in both resistance to oxidation and amount of oxidation required to produce rancidity. Primarily for this reason, natural fats containing antioxidants are much more resistant to oxidation than their pure triglyceride counterparts.
Since unsaturated fat and fatty acid components of an oil composition, such as triglycerides, diglycerides, alkoxydiglycerides (i.e., glycerol ethers), monoglycerides, omega-3 fatty acids, omega-9 fatty acids and the like, are susceptible to oxidation when exposed to air, the absence of these natural antioxidants from the oil composition leads to a decrease in the stability thereof. Bailey's Industrial Oil and Fat Products defines stability "as the resistance to autoxidation under prescribed conditions of aging . . . measured in units of time required for the product to (a) acquire a state of oxidation which can be correlated with organoleptic detection of rancid odor and flavor, or (b) to reach the end of the induction period if oxygen absorption measurement or peroxide analysis is used." The induction period is the time frame in which antioxidants effectively protect against oxidation. Once rapid oxidation sets in, antioxidants have little or no ability to curtail the reaction. Consequently, the presence of antioxidants in a composition constitutes a preventive measure rather than a corrective one.
Decomposition via oxidation can also cause a decrease in the percentage of unsaponifiable matter contained in an oil composition through oxidative degradation of hydrocarbons. Saponification is the reaction of a fatty acid, for example, with a base to produce a salt. Hydrocarbons, for example, cannot undergo such a reaction and are, thus, unsaponifiable. Exemplary unsaponifiable hydrocarbons found in oil compositions are squalene, gaducene, pristane, zamene, citorhenene and the like. The hydrocarbon squalene exhibits antioxidant activity under certain circumstances. Squalene also enhances percutaneous absorption of vitamin A and serves as a protective agent for human sebum. Other exemplary unsaponifiable components of fish oil are sterol, methyl sterol, long-chain alcohol, triterpene alcohol, pigment, trace materials, and the like.
Topical compositions are typically stored for some time prior to application thereof, and often are left standing open by users between such applications. Thus, stability of each component within a topical composition is considered in assessing the usefulness of the topical composition as a whole. A decrease in the stability of any component decreases the utility of the topical composition in which the component is dispersed. Moreover, antioxidants are not compound-specific protectants. That is, tocopherols dispersed in a topical composition would protect fatty acids, hydrocarbons and any other oxidation-susceptible component of that topical composition from oxidation. Thus, chemical deodorization of the oil composition can create stability problems for the topical product containing the oil composition by functionally impairing or destroying natural antioxidants.
Other, non-fatty acid components of an oil composition, such as vitamins, pro-vitamins (i.e., precursors of vitamins which are converted to vitamins in vivo), neovitamtns (i.e., isomeric forms of vitamins that function as vitamins in vivo), sterols, phosphatides, hydrocarbons and the like, may also be removed, functionally destroyed or functionally impaired during the deodorization or other oil processing. Alkali refining, for example, may significantly reduce the vitamin A content of oils, and carbon treatment of the oil composition may render the vitamin A component unstable. Hydrogenation processing may saturate vitamin A and decrease the biological activity thereof, unless precautions to preserve vitamin A activity are taken. Also, high temperature treatments, such as steam deodorization, decompose vitamin A provitamins.
These additional oil composition components, if intact, may also contribute other desirable properties to the topical composition as a whole. For example, vitamins, such as vitamin D and vitamin A, often significant components of oil compositions, serve certain biological functions. Vitamin E exhibits antioxidant properties as well as other vitamin E activity. Further, interrelation hips between the functions of vitamin A and vitamin E have been noted and attributed, in part, to the protective action of vitamin E with respect to vitamin A. Sterols, such as cholesterol, impart sterol activity in vivo. Phosphatides provide reinforcement to the action of other antioxidants.
It has now been recognized in the present invention that a substantially intact oil composition (i.e., a composition in which the components thereof are maintained in a form substantially equivalent to the natural form of those components) imparts advantageous properties to the ultimate topical composition containing the oil composition. The natural form of each of the components of the oil composition ingredient of the ultimate topical composition of the present invention is that form in which those components exist prior to refining. When chemical deodorizing processes are used, such components are modified and, as a result, chemical deodorization adversely impacts the ability of the oil component of the topical composition to impart advantageous properties to the ultimate topical composition.
Moreover, the natural form of the oil composition components typically includes one or more specific isomeric forms thereof. Other isomers may be created through oxidation, hydrogenation, partial hydrogenation, high temperature treatments and the like. For example, U.S. Pat. No. 4,843,095 indicates that saponification reactions converting triglyceride oil components to free fatty acids, if conducted under certain conditions, result in isomerization via cis-trans conversion. That is, the fatty acids resulting from the reaction do not correspond isometrically to the original triglyceride starting material. In addition, prior oil containing compositions were stabilized by hydrogenating the oil. It has now been discovered that hydrogenated fatty acids exhibit inferior penetration abilities in comparison with the natural polyunsaturated form of the fatty acids.
Estimates indicate that more than 35,000,000 U.S. adults and children suffer from pain. Some of these sufferers exhibit concomitant inflammatory conditions such as rheumatoid or psortatic arthritis. Other patients, however, do not fall into the inflammation category, but have a wide variety of musculoskeletal ailments including myofascial pain syndrome, tendoniris, bursitis, ligament attachment conditions or soft tissue complaints. An additional subset of patients exhibit chronic low-back pain that is not inflammatory but, nevertheless, requires pain management. Short-lived acute problems, such as tennis elbow, bursiris, and hip pointers, would also benefit from some form of pain management. Post trauma pain sufferers who have sustained ligamentous tears, miniscal tears, contusions, fractures or the like are another important patient subset. Metabolically-caused pain (i.e., gout, pseudogout, osteoporosis, primary underlying bone disease such as Paget's disease) requires management. In addition, treatment of patients with primary or secondary cancer are problematic for the clinician in view of these patient's pain management needs.
Almost all of the aforementioned patients suffering pain will be treated by physicians with nonsteroidal anti-inflammatory drugs, consisting primarily of chemical variations of ibuprofen. Regardless of the length of the half-lives of these routinely used drugs, administration thereof can result in serious undesirable side-effects. Estimates indicate that approximately 5% of the patients who receive these drugs will develop an NSAID-induced gastropathy that can lead to peptic ulceration, bleeding, hemorrhage, and even death. Moreover, patients in this 5% bracket are asymptomatic, and, as a result their first presentation to a hospital typically results from a GI hemorrhage. Other problems which may arise from the administration of anti-inflammatory drugs are compromised renal function, dermatological or cutaneous reactions, drug-induced hepatitis, enhanced salt retention, and, in rare cases, potentially fatal bone marrow depression. Patients with high blood pressure must be monitored carefully when being treated to manage pain, because the patient's hypertension may be augmented by the pain medication. Also, pain treatment available to children are severely limited as a result of the side-effects of these anti-inflammatory medications.
Given the problems incumbent in this entire class of medication, it is desirable to provide a therapeutic option allowing effective pain management with decreased risk of deleterious side-effects. It has been recognized by the present inventors that topical administration of anti-inflammatory agents may provide such an alternative. When administered directly to the afflicted area, high levels of the medicament may be directly delivered to produce a significant therapeutic response.
Thus, preparations containing oils or fractions or combinations thereof, which do not exude the unpleasant odor characteristic of such oils or oil fractions or combinations would be useful. In addition, since it has now been recognized that topical compositions containing oil compositions, with the components thereof maintained in their naturally occurring state stably therein (i.e., exhibiting no substantial chemical breakdown or alteration of those oil components) offer advantages over topical compositions containing conventionally processed oil compositions, maintenance of the components of an oil composition ingredient of a topical composition in a form substantially the same as its natural form during and after deodorization is desireable.